Ludger M. Ickenstein

Nuclisome: a novel concept for radionuclide therapy using targeting liposomes

PurposeFor the treatment of cancer, the therapeutic potential of short-range, low-energy Auger-electron emitters, such as 125I, is getting progressively wider recognition. The potency of Auger-electron emitters is strongly dependent on their location in close vicinity to DNA. We have developed a new two-step targeting strategy to transport 125I into cancer-cell nuclei using PEG-stabilized tumour-cell targeting liposomes named “Nuclisome-particles”.MethodsIn the present study, epidermal growth factor (EGF) was used as a tumour-cell-specific agent to target the EGF-receptor (EGFR) and the liposomes were loaded with 125I-Comp1, a recently synthesized daunorubicin derivative.ResultsAs analysed with cryo-TEM, the derivative precipitates inside liposomes at a drug-to-lipid molar ratio of 0.05:1. Receptor-specific uptake in cultured U-343MGaCl2:6 tumour cells of EGFR-targeting liposomes increased with time while non-specific and receptor-blocked uptake remained low. Nuclisome-particles were able to target single U-343MGaCl2:6 cells circulating in human blood during 4 h, with low uptake in white blood cells, as demonstrated in an ex vivo system using a Chandler loop. Autoradiography of targeted cells indicates that the grains from the radiolabelled drug are mainly co-localized with the cell nuclei. The successful targeting of the nucleus is shown to provide high-potency cell killing of cultured U-343MGaCl2:6 cells. At the concentration used, Nuclisome-particles were up to five orders of magnitude more effective in cell killing than EGFR-targeting liposomes loaded with doxorubicin.ConclusionThe results thus provide encouraging evidence that our two-step targeting strategy for tumour cell DNA has the potential to become an effective therapy against metastasizing cancer cells in the bloodstream.

The Development of Liposomes for Enhanced Delivery of Chemotherapeutics to Tumors

Liposomes were first discovered in the 1960s by Bangham, who observed that ordered spherical membranes spontaneously formed when dried lipids were hydrated into aqueous solutions (1). The potential utility of these carrier systems for the delivery of therapeutic agents to disease sites has continually evolved since this initial observation. In order for liposomes to be considered as a viable pharmaceutical-delivery system, many issues needed to be resolved including efficient drug encapsulation, liposome stability, and the production of homogeneous liposome populations. These obstacles were overcome in the 1980s with the development of various liposome-production procedures including extrusion (2), dialysis (3), homogenization (4), and dehydration/rehydration techniques (5). Currently, the most commonly used process is extrusion due to its ease of usage, simplicity, speed, and reproducibility.

Tamoxifen Alters Hepatic Cytochrome P450 Enzyme Expression and Circulating Growth Hormone Levels in Intact Male Rats

AbstractPurpose. To investigate the effects of acute tamoxifen treatment on hepatic cytochrome P450 (CYP) expression and circulating thyroid and growth hormone (GH) levels in intact adult male rats. Methods. Rats were injected subcutaneously with peanut oil (vehicle) or tamoxifen at a dosage of 20 or 200 mg/kg for 2 consecutive days. Blood for GH measurements was collected on day 34. Rats were sacrificed at 37 days after treatment, trunk blood was collected, and hepatic microsomes were prepared. Results. Mean body weight of rats treated with tamoxifen at 200 mg/kg was decreased compared to vehicle-treated rats throughout the 5-week period after treatment. Hepatic CYP2A1-dependent testosterone 7α-hydroxylase activity and CYP2A1 protein content were increased, whereas CYP2C11-mediated testosterone 2α- and 16α-hydroxylase activities and CYP2C11 protein content were decreased significantly following tamoxifen administration. Peak plasma GH levels were 60% lower and nadir plasma GH levels were 30% higher in tamoxifen-treated relative to vehicle-treated rats. In contrast, serum triiodothyronine and thyroxine levels were not affected by tamoxifen treatment. Conclusions. Hepatic CYP enzyme expression was altered and body weight was decreased in adult male rats 5 weeks after treatment with tamoxifen. This alteration corresponded to changes in plasma GH levels.